Project Summary/Abstract microRNAs (miRNAs) act as negative regulators of gene expression by inhibiting the translation or promoting the degradation of target mRNAs. Recent studies by our group and others have revealed profound and unexpected roles for miRNAs in the control of diverse aspects of cardiac function, including the control of myocyte growth, integrity of the ventricular wall, contractility, gene expression, and maintenance of cardiac rhythm, providing glimpses of undiscovered regulatory mechanisms and potential therapeutic targets for heart disease. Specific miRNAs are mis-expressed in diseased hearts, and gain and loss-of-function experiments in mice have shown these miRNAs to be necessary and sufficient for multiple forms of heart disease. Particularly fascinating is the discovery of a family of closely related miRNAs that are encoded by introns of myosin heavy chain genes. In the heart, these miRNAs control myosin expression, stress dependent growth and fibrosis, thyroid hormone responsiveness, and repress fast skeletal muscle gene expression. In skeletal muscle, a subset of these miRNAs regulates fast versus slow myofiber identity. We refer to these miRNAs and the myosin genes in which they are embedded, as the Myo-miR network. The Myo-miR network, which is evolutionarily conserved, is regulated by upstream signaling pathways and modulates downstream targets through mechanisms that are only beginning to be unveiled. The overall goal of this project is to define the molecular mechanisms whereby the Myo-miR network modulates cardiac and skeletal muscle function, development and disease. Ultimately, we hope to exploit our understanding of miRNA biology to uncover new disease mechanisms and therapeutic approaches for muscle disease.